Emergence of co-expression in gene regulatory networks

Transcriptomes are known to organize themselves into gene co-expression clusters or modules where groups of genes display distinct patterns of coordinated or synchronous expression across independent biological samples. The functional significance of these co-expression clusters is suggested by the fact that highly coexpressed groups of genes tend to be enriched in genes involved in common functions and biological processes. While gene co-expression is widely assumed to reflect close regulatory proximity, the validity of this assumption remains unclear. Here we use a simple synthetic gene regulatory network (GRN) model and contrast the resulting co-expression structure produced by these networks with their known regulatory architecture and with the co-expression structure measured in available human expression data. Using randomization tests, we found that the levels of co-expression observed in simulated expression data were, just as with empirical data, significantly higher than expected by chance. When examining the source of correlated expression, we found that individual regulators, both in simulated and experimental data, fail, on average, to display correlated expression with their immediate targets. However, highly correlated gene pairs tend to share at least one common regulator, while most gene pairs sharing common regulators do not necessarily display correlated expression. Our results demonstrate that widespread co-expression naturally emerges in regulatory networks, and that it is a reliable and direct indicator of active co-regulation in a given cellular context.

Apontic regulates cell proliferation and development by activating the expression of hedgehog and cyclin E

ABSTRACTHedgehog (Hh) signaling pathway and Cyclin E are key players in cell proliferation and development. Hyperactivation of hh and cyclin E. has been linked to several types of cancer. However, transcriptional regulation of hh and cyclin E. are not well understood. Here we show that an evolutionarily conserved transcription factor Apontic (Apt) is an activator of hh and cyclin E. in Drosophila. Apt directly promotes the expression of hh and cyclin E. through its binding site in the promoter regions of hh and cyclin E. during wing development. This Apt-dependent proper expression of hh and cyclin E. is required for cell proliferation and development of the wing. Apt-mediated expression of hh and cyclin E. can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. The discovery of the coordinated expression of Hh and principal cell-cycle regulator Cyclin E. by Apt implicates insight into the mechanism by which deregulated hh and cyclin E promotes tumor formation.Summary statementWe identified a novel role for Apontic as an important common regulator of the transcription of hedgehog and cyclin E. Our study provides important insights into the mechanism of organ development.

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.